Nisoldipine, chemically known as 3,5-pyridinedicarboxylic acid-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-methyl-2-methyl-propyl ester, belongs to the dihydropyridine class of calcium channel blockers and is approved for the treatment of hypertension, either alone or in combination with other antihypertensive agents.
Nisoldipine was first disclosed by Wehinger et al in U.S. Pat. No. 4,154,839 and is marketed in USA and worldwide under the brand name SULAR® as an extended release formulation. Initially, the marketed extended release oral formulations of SULAR® were available in 10, 20, 30 and 40 mg strengths. However, subsequently these formulations were replaced with a lower strength formulation of Nisoldipine and presently the marketed nisoldipine formulations are available as extended release tablets in 8.5, 17, 25.5 and 34 mg strengths. These are available as multi-layered tablets with top and bottom barrier layers and a middle layer of active ingredient, Nisoldipine.
Dihydropyridines pharmaceuticals such as nisoldipine, which have very low solubility in water, pose serious difficulties in preparation of formulations. This is attributed to their poor rate and extent of dissolution in aqueous media and gastrointestinal fluids, which ultimately results in low absorption in the systemic circulation after oral ingestion.
Therefore, different approaches have been used in the prior art for making formulations of sparingly soluble dihydropyridines such as nisoldipine. Ohm et al in U.S. Pat. No. 4,892,741 discloses a press coated tablet comprising a core which contains dihydropyridine in a rapid release form and a coat around it with a dihydropyridine in a slow release form.
Conte et al in U.S. Pat. No. 5,626,874 discloses a controlled release pharmaceutical tablet, having a lenticular form consisting of the three over-imposed layers. The disclosed formulation has a central layer or core comprising an active principle and two external barrier layers upon and under said core layer limiting the active principle release.
Vergnault et al in WO2008/025535 discloses a multi layered controlled release oral dosage formulation for Nisoldipine wherein the core contained the active ingredient along with an enteric agent while the barrier layers comprised swellable, gellable or erodible polymers.
Maggi et al in U.S. Pat. No. 6,221,395 discloses a pharmaceutical tablet for oral administration, which is able to release under controlled speed, the active principles having low solubility. The document discloses use of particular concentrations of surface active agents in a hydrophilic matrix in order to enhance the dissolution speed of a poorly soluble drug and one or more barrier layer surrounding the active layer.
Further, Prasad et al in US 2010/247646 discloses an extended release tablet comprising a core of nisoldipine, a hydrophilic polymer optionally, an enteric agent and a release rate-controlling coating comprising a hydrophobic polymer, an enteric agent or a combination thereof surrounding the said core.
Thus, the prior art formulations exhaustively relates to multilayer tablet formulations which comprise a top barrier layer, a middle layer containing active therapeutic agent and a bottom barrier layer for preparing an extended release formulation of nisoldipine. Although, these formulations can provide an extended release formulation, but the requirement of complex machinery and processing for tableting renders their manufacturing, an expensive and time-consuming process making them commercially not particularly viable.
Therefore, there exists a need for an extended release formulation for nisoldipine which is convenient and simple to manufacture.